Synthesis and structural analysis of the copper(II) complexes of N2-(2-pyridylmethyl)-2-pyridinecarboxamide

• Published in: Journal of inorganic biochemistry 2001-09, Vol.86 (2), p.547-554
• Main Authors: Lebon, Florence, Ledecq, Marie, Dieu, Marc, Demazy, Catherine, Remacle, José, Lapouyade, René, Kahn, Olivier, Durant, François
• Format: Article
• Language: English
• Subjects: Catalytic Domain; Copper - chemistry; Crystallography, X-Ray; Drug Design; ESI-MS; HIV Protease - chemistry; HIV Protease Inhibitors - chemical synthesis; HIV Protease Inhibitors - chemistry; HIV Protease Inhibitors - pharmacology; HIV-1 PR; In Vitro Techniques; Inhibitors; Metal–organic complexes; Models, Molecular; Organometallic Compounds - chemical synthesis; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Spectrometry, Mass, Electrospray Ionization
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/S0162-0134(01)00219-7

Previous investigations of the potential of metal–organic compounds as inhibitors of human immunodeficiency virus type I protease (HIV-1 PR) showed that the copper(II) complex diaqua [bis(2-pyridylcarbonyl)amido] copper(II) nitrate dihydrate and the complex bis[ N2-(2,3,6-trimethoxybenzyl)-4-2-pyridinecarboxamide] copper(II) behaved as inhibitors of HIV-1 PR. In a search for similar readily accessible ligands, we synthesised and studied the structural properties of N2-(2-pyridylmethyl)-2-pyridinecarboxamide (L) copper(II) complexes. Three different crystal structures were obtained. Two were found to contain ligand L simultaneously in a tridentate and bidentate conformation [Cu(L triL bi)]. The other contained two symmetry-related ligands, coordinated through the pyridine nitrogen and the amide oxygen atoms [Cu(L bi) 2]. A search of the Cambridge Structural Database indicated that L tri resulting from nitrogen bound amide hydrogen metal substitution is favoured over chelation through the amide oxygen atom. In our case, we calculated that the conformation of L tri is 11 kcal/mol more favourable than that of L bi. ESI-MS experiments showed that the Cu(L bi) 2 structure could not be observed in solution, while Cu(L triL bi)-related complexes were indeed present. The lack of protease inhibition of the pyridine carboxamide copper(II) complexes was explained by the fact that the Cu(L biL tri) complex could not fit into the HIV-1 active site.